Keratoconus is the most common corneal degeneration in the US, affecting about 1 in 2000 people with a mean onset age of 15.4 years. The organization of collagen fibers in the cornea provides the mechanical strength that is essential to support the load and form the normal corneal shape. In keratoconus, the microstructural changes in the cornea disrupt the mechanical stability. Keratoconus explants showed disrupted collagen orientation and decreased mechanical modulus. Current diagnosis relies on indirect factors such as age and corneal geometrical features and thus far has failed to allow definitive diagnosis of early-stage progressive keratoconus. The proposed research will use recently developed Brillouin microscopy to test the hypothesis that spatially localized degeneration of mechanical stability is a critical driver of keratoconus progression. The first specific aim will improve the accuracy and speed of the current Brillouin instrument to enable comprehensive mechanical mapping of the cornea from patients with subclinical, mild, and advanced keratoconus. The second specific aim will determine the correlation between various biomechanical metrics derived from the in vivo measurements and the rate of progression of morphological changes. The third specific aim will derive model-based diagnostic metrics that are quantitatively related to corneal mechanical instability and correlated with the clinical data. The proposed study is expected to have high impacts on the clinical management of keratoconus patients by providing biomechanical metrics in vivo that will allow objective assessment of the rate of progression of keratoconus prospectively in early stages and enable clinicians to make objective, timely decision for optimal treatments of progressive keratoconus. Moreover, the research will accelerate the translation of the Brillouin technology to the clinic.